Clinically useful molecular probes, including isotopically labeled probes, are an integral component of nuclear medicine, and offer a non-invasive approach to detecting disease, diagnosis, staging, restaging, and therapeutic management. Molecular probes using medical isotopes are used in a variety of disorder, including neurological and oncological diseases.
Positron- and Single Photon-Emitting Radiopharmaceuticals (PERs and SPERs) have evolved as preferred diagnostic tools since they contain short-lived radionuclides (e.g., T1/2, F-18=110 min; C-11=20 min), offering high image resolution and less radiation damage to the non-targeted body tissues because of the faster decay of the radioisotope.
The decay properties of the various radioisotopes of iodine offer trimodal (diagnosis, chemotherapy, and in situ in vivo molecular radiotherapy (MRT), e.g., by *IAZA [*I=123/124/125/127/131]I) versatility to radioiodinated pharmaceuticals. No other element has isotopes suitable for SPECT/planar imaging (123/131I), PET imaging (124I) and radiotherapy (MRT; 124/125/131I). Using only one labeling element (i.e., iodine) also ensures that no metabolic or biochemical properties are modulated when moving from one modality to another. In brief, these radiopharmaceuticals can play a significant role in the theranostic (therapy+diagnostic) management of hypoxic diseases.
Such PER and SPER imaging systems create images based on the distribution of radiation-emitting radiopharmaceuticals in the body of a patient. The isotopes are typically administered to a patient by injection of probes (molecules) that comprise radiation-emitting radionuclides, such as F-18, C-11, N-13, O-15 or I-123, covalently attached to a molecule that is readily metabolized or localized in cells, or that chemically binds to macromolecules (i.e., receptors, enzymes) within cells. In some cases, the probe is administered to the patient as an ionic solution, metal chelate or by inhalation.
In some cancers, cell growth can develop in poorly vascularized, ischemic environments. Such environments that are removed from the vasculature or are poorly vascularized can become hypoxic, characterized by low tissue pO2 levels.
Tissue hypoxia results from temporary or persistent ischemia (inadequate oxygen supply) (1). In tumors, hypoxia induces adaptive transcriptional and post-translational changes promoting the development of an aggressive phenotype which induces metastatic potential, promotes angiogenesis and supports local disease progression (1-5). Hypoxic tumors are clinically problematic as they can be resistant to both radiation therapy and/or cytotoxic therapy, which can result in treatment failure and poor outcomes. Therefore, assessing the level of tumor hypoxia may play a significant role in the outcome of the treatment and the therapy management of the cancer patients. Because hypoxic tumors respond poorly to both traditional radiation and cytotoxic therapies, identification of hypoxic tumors may indicate alternate approaches exist for treating hypoxic cancer cells.
Several techniques have been developed to measure the presence and extent of tumor hypoxia in vivo, ex vivo and in vitro. Determining tumor hypoxia via electrode measurements of pO2 concentrations within the tumor is impractical in the clinical setting. The refinement of positron emission tomography (PET) techniques, with the advantage of short half-life positron-based radionuclides, and the development of hypoxia-specific positron emitting radiopharmaceuticals (PERs) have made PET a preferred non-invasive functional technique for clinical hypoxia imaging (7-9). Several PET and SPET nitroimidazole-based radiosensitizers (specifically, e.g., FAZA, IAZA) have been explored for scintigraphic imaging of hypoxia (10, 11); in the presence of low intracellular oxygen levels, they form adducts with hypoxic cellular macromolecules as the basis for their hypoxia-selective accumulation, and hence imaging properties. Nitroimidazole-based molecules demonstrate optimal reduction potentials for hypoxia-selective reductive binding that leads to their accumulation specifically and selectively in hypoxic tumor cells (12-17), and radioiodinated (*IAZA) and radiofluorinated ([18F]-FAZA; [18F]FAZA; 18F-FAZA 18FAZA) azomycin arabinosides are examples of 2-nitroimidazole (azomycin) nucleosides-based clinical radiopharmaceuticals that have gained extensive popularity for SPECT/PET-imaging and therapy management of hypoxic tissues.
Based on this hypoxia-selective retention, halogenated nucleoside derivatives of azomycin will selectively radiosensitize hypoxic cells to external beam x-ray radiotherapy (XRT), and when labeled with the appropriate radioiodine (*I) they will enable imaging-based discovery and assessment of hypoxic tissue (123/124I) and delivery of therapeutic doses (124/131I) of ionizing radiation to hypoxic tumors in situ in vivo (MRT); (3) Rapid clearance of these molecules from non-target tissues, an essential feature of drugs used for MRT (to reduce the radiation burden to non-target tissues) and radiosensitization (to reduce non-target dose-limiting toxicities), will reduce dose-limiting toxicities to the healthy tissues.
1-α-D-(5-deoxy-5-[*I]-iodoarabinofuranosyl)-2-nitroimidazole (*IAZA) and, 1-α-D-(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole (18FAZA), have been developed at the Cross Cancer Institute (CCI), Edmonton, Alberta, Canada (18) for their use in the diagnosis and potential therapy of hypoxic tumors (Kumar et al, 2005, Kumar et al 1998). 18FAZA is currently being used clinically in human cancer patients globally as a PET radiodiagnostic to assess the level of hypoxia in solid tumors and develop improved treatment plans (18-20). Preclinical studies have shown that 18FAZA, is rapidly cleared from the circulation and non-hypoxic tissues, and is excreted mainly via the renal pathway, thereby providing more favourable tumor-to-background ratios in most anatomical regions (21). In contrast, [18F]-FMISO (22), a chemically-related but highly lipophilic clinical PET tracer in hypoxia management, is cleared primarily through the hepatobiliary route and undergoes non-specific lipoidal uptake in brain, liver and other organs, thereby interfering with the image quality in these regions of interest (23). Increasing clinical demands for 18FAZA (20, 24-27) requires the development of an improved and facile manufacturing process that could afford this product and other products of this class inexpensively and without much complication in the synthesis.
Typically, the synthesis of such probes requires a suitable precursor/synthon, and desirably an overall simple reaction quality of the radiolabeled mixture (e.g., minimal side products formation), short manufacture time, higher specific activity and/or the radiochemical yields since an inferior production process adversely affects the development.
It is therefore desirable to provide compositions and/methods for providing suitable precursors and/or methods for synthesizing such precursors. Such precursors can be incorporated into kits that are compatible with commercially available synthesis units, such as the GE Tracerlab etc., to produce PET radiotracers.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention.